Mitochondrial tRNA Mutations are Associated with Maternally Inherited Hypertension in two Han Chinese Pedigrees

We report here the clinical, genetic, molecular, and biochemical evaluations in two Han Chinese families with maternally inherited hypertension. Fourteen of 20 adult matrilineal relatives of these families exhibited a wide range of severity in hypertension, while none of offspring of affected fathers had hypertension. The age-at-onset of hypertension in matrilineal relatives varied from 37 years to 83 years, with an average of 55 and 66 years, respectively. Mutational analysis of their mitochondrial genomes identified the m.4353T>C mutation in the tRNA, in conjunction with the known m.593C>T mutation in the tRNA(Phe) and m.5553C>T mutation in the tRNA(Trp). Northern analysis revealed that m.4353T>C, m.593C>T and m.5553C>T mutations caused similar to 66%, 65%, and 12% reductions in the steady-state level of tRNA(Gln), tRNA(Phe) and tRNA(Trp), respectively. An in vivo protein labeling analysis showed similar to 35% reduction in the rate of mitochondrial translation in cells carrying these tRNA mutations. Impaired mitochondrial translation is apparently a primary contributor to the reduced rates of overall respiratory capacity, malate/glutamate-promoted respiration, succinate/glycerol-3-phosphate-promoted respiration, or N,N,N',N'-tetramethyl-p-phenylenediamine/ascorbate-promoted respiration and the increasing level of reactive oxygen species in the cells carrying these mtDNA mutations. These data demonstrate that mitochondrial dysfunction caused by mitochondrial tRNA mutations is associated with essential hypertension in these families. Hum Mutat 33:1285-1293, 2012. (c) 2012 Wiley Periodicals, Inc.